1. Information Relating to Previous Patents and Applications
Several aminosterol compositions have been isolated from the liver and stomach of the dogfish shark, Squalus acanthias. One important aminosterol, squalamine, is the subject of U.S. Pat. No. 5,192,756 to Zasloff, et al., which patent is entirely incorporated herein by reference. That patent describes the antibiotic properties of squalamine. Since the discovery of squalamine, several interesting properties of this compound have been discovered. For example, as described in U.S. patent appl. Ser. No. 08/416,883 (filed Apr. 20, 1995) and U.S. patent application Ser. No. 08/478,763 (filed Jun. 7, 1995), squalamine may function as an antiangiogenic agent. These patent applications are entirely incorporated herein by reference. Additional uses of squalamine (e.g., as an NHE3 inhibiting agent and as an agent for inhibiting the growth of endothelial cells) are disclosed in U.S. patent appl. Ser. No. 08/474,799 (filed Jun. 7, 1995) and U.S. patent appl. Ser. No. 08/840,706 (filed Apr. 25, 1997, entitled "Treatment of Carcinomas Using Squalamine in Combination with Other Anti-cancer Agents," in the names of Michael Zasloff and Jon Williams). These applications also are entirely incorporated herein by reference.
Methods for synthesizing squalamine have been devised, such as the methods described in WO 94/19366 (published Sep. 1, 1994) and in U.S. patent appl. Ser. No. 60/032,378. This PCT publication and the U.S. patent application are entirely incorporated herein by reference. The PCT application relates to U.S. patent appl. Ser. No. 08/023,347, which application also is entirely incorporated herein by reference. Additionally, U.S. patent appl. Ser. No. 08/474,799 also discloses squalamine isolation and synthesis techniques.
Stemming from the discovery of squalamine, other aminosterols have been discovered in the dogfish shark liver and stomach and have been investigated. One important aminosterol that has been isolated and identified has the structure shown in FIG. 1. In this application, the compound having the structure shown in FIG. 1 will be referred to as "compound 1436" or simply "1436." This compound has the general molecular formula C.sub.37 H.sub.72 N.sub.4 O.sub.5 S and a calculated molecular weight of 684.53017.
Compound 1436 previously has been described in U.S. patent appl. Ser. Nos. 08/483,057; 08/479,457; and 08/487,443, each filed Jun. 7, 1995. Each of these U.S. patent applications is entirely incorporated herein by reference. These U.S. patent applications describe the structure of compound 1436 and other aminosterols, as well as processes for synthesizing and isolating compound 1436 and other aminosterols. For example, compound 1436 may be prepared from a squalamine starting material. Additional methods for synthesizing compound 1436 (as well as squalamine) are described in U.S. Provisional patent appl. Ser. No. 60/032,378, filed Dec. 6, 1996, which application is entirely incorporated herein by reference.
As further described in these patent applications, compound 1436 has a variety of interesting properties. For example, compound 1436 has been found to be capable of inhibiting mitogen-induced mouse, dog or human T-lymphocyte proliferation, as well as being capable of inhibiting the proliferation of a variety of other cells and tissues.
2. Information Relating to this Application
Compound 1436 and other aminosterol compounds isolated from the dogfish shark liver and stomach have been found to possess interesting antibiotic and anti-proliferative properties with respect to a variety of cells and tissues. These interesting properties of compound 1436 have prompted applicants to conduct further investigation into the uses and properties of this compound.
It has been found that compound 1436 has antiviral effects on several viruses. For example, compound 1436 has been found to inhibit replication of the human immunodeficiency virus ("HIV") in accepted tissue culture models. In addition to its inhibitory effect on HIV, compound 1436 also inhibits replication of the simian immunodeficiency virus ("SIV") in tissue culture. Based on these properties, applicants conclude that compound 1436 has immunomodulatory and antiviral effects. As an additional example of its antiviral activity, applicants have determined that compound 1436 is effective in inhibiting replication of the herpes simplex virus ("HSV").
In addition to its favorable antiviral activity, applicants have found that compound 1436 also has anti-proliferative effects that assist in the treatment of various types of cancer. The growth of various different types of cancer tumors is inhibited by treatment with compound 1436. Applicants have found, for example, that proliferation of human melanoma cells is inhibited by compound 1436 even after relatively short treatment times. Additionally, compound 1436 has been found to be effective in treating leukemias, such as murine acute lymphocytic leukemia (murine "ALL") and human myeloid leukemic cells growing in a mouse xenograft model.
Applicants have found still further uses for compound 1436. It has been found that delayed type immune hypersensitivity and arthritis also may be effectively treated using compound 1436. In mouse models, the use of compound 1436 was found to significantly reduce paw swelling in mice that were induced to develop arthritis.
In addition to treating various ailments and diseases, such as viral based ailments and diseases, cancers, and arthritis, compound 1436 has been found to have other favorable properties and effects. As one specific example, applicants have found that compound 1436 may be used to reduce weight gain in mammals. The weight gain of the animals in these studies was controlled due to reduction of net fluid intake. The animals continued to have normal food consumption and were apparently healthy, viable animals.
The loss of fluid upon 1436 administration was found by the inventors to involve a commensurate loss of electrolytes in animals. The compound 1436 may, therefore, be useful in therapeutic settings where diuresis is desirable, such as congestive heart failure, nephrotic syndromes, post-surgical hypervolemia, hepatic cirrhosis, cerebral edema secondary to head trauma, or lymphedema.